After more than 40 years dopaminergic substitution with the dopamine precursor levodopa remains the mainstay for the symptomatic treatment of Parkinson's disease (PD) [1]. Levodopa side effects are mainly dopaminergic and include: nausea, ortho-static hypotension, hallucination, sedation, daytime somnolence, vomiting, delusions, and psychosis. Besides its key role as neuro-transmitter, dopamine is a crucial transmitter in the neuroimmune network [2,3]. So far however no immune effects of levodopa have been documented, although the product monographs of levodopa-containing medicines list leukopenia and agranulocytosis among rare adverse reactions. We report the case of a PD patient with levodopa-induced neutropenia and reduced D 2-like dopaminergic receptors (DR) D 2 , D 3 , and D 4 and increased D 1-like DRD 5 and TH in circulating neutrophils. In January 2009 an 82-year-old caucasian man, without previous personal or family history of neurological or hematological disease , was admitted for progressive resting tremor. He denied allergic reactions or drug intolerance and was on the following medications since several years without any adverse reactions: tamsulosin, dutasteride, escitalopram, aspirin. Neurological examination showed right upper limb resting tremor, micrographia, slight diffuse hypokinesia, left arm decreased physiological synci-nesis. DaT-SPECT imaging showed bilateral striatal dopaminergic deficit. In June 2010 he presented with reduced motor autonomies, gait difficulties and festination, and levodopa/carbidopa 100/25 mg 2 cp/die was started with clinical benefit. Five months later however a routinary control showed reduced leukocytes with neutropenia (0.93 Â 10 9 cells/L, normal values: 1.5e7 Â 10 9 cells/L). Leukopenia was confirmed three weeks later and the patient underwent an haematological evaluation. The consultant haematologist excluded other causes of neutropenia based on the general medical evaluation and blood test values. Moreover no other new drugs were prescribed to the patients in the two months preceding the development of neutropenia. Levodopa/carbidopa was suspended , with neutrophil count normalization 2.5 months later. Levodopa/benserazide 100/25 mg 2 cp/die was thus initiated, however after one month neutropenia (0.98 Â 10 9 cells/L) arised and persisted even after dose reduction to 1 cp/die. Levodopa/benserazide was eventually withdrawn and pramipexole 0.7 mg 1 cp/die was started. After 4 months neutrophil count was within normal limits (1.89 Â 10 9 cells/L) and pramipexole provided clinical benefit and no evidence of adverse effects. During this period, the patient was asymptomatic for leukopenia-related symptomatology. The time course of leukocyte and neutrophil count in relation to levodopa administration is shown in Fig. 1A while his complete blood counts are shown in Table 1. Written informed consent was obtained. Levels of mRNA for DR and for TH in circulating neutrophils were measured according to a published method [3] based on blood taps performed while the patient was still on levodopa therapy. In comparison to neutrophils of 10 healthy controls, neutrophils of the PD patient had all the D 2-like DR lower than the lowest control values, and the D 1-like DRD 5 and TH higher than the highest control values (Fig. 1B). To our knowledge, this is the first report describing levodopa-induced neutropenia. According to the WHO criteria for causality assessment (http://who-umc.org/Graphics/26649.pdf, accessed August 30th, 2014), the relationship between levodopa and neutro-penia is probable/certain, and a role for DDC inhibitors can be excluded since neutropenia arised with both levodopa/carbidopa and levodopa/benserazide. Based on available knowledge, the cellular and molecular mechanisms underlying levodopa-induced neutropenia can be just hypothesized, and several possibilities could be considered. First, neutrophils might be directly affected by levodopa or dopamine. As regards the possible direct effects of levodopa on neutrophils, no evidence exists with the only exception of a report showing morphological changes of human neutrophils after in vitro exposure to levodopa [4], however its biological significance is uncertain. Dopamine on the contrary has been shown in vitro to directly induce apoptosis of human neutrophils [5]. Moreover, evidence exists supporting a role for dopamine also in the regulation of hematopoiesis. Indeed, murine bone marrow contains substantial amounts of noradrenaline and dopamine, which exhibit a daily rhythmicity [6], and human CD34 þ cells in cord blood and in peripheral blood express DR D3 and DR D5 on their surfaces, which are upregulated by exposure to G-CSF [7]. Neutrophils from our patients had decreased D 2-like DR and increased D 1-like DRD 5 and TH. Whether changes are due to PD and/or to drugs cannot be established, nonetheless the finding possibly highlights a peculiar sensitivity to dopaminergic agents, biased towards D 1-like DR-operated pathways. The patient was finally prescribed pramipexole, a D 2-like DR agonist with negligible affinity for D 1-like DR, with clinical benefit and no evidence of hematological or other adverse effects, thus excluding a role for D 2-like DR. Neutropenia represents 0.9% of all adverse reactions to levodopa-containing medicines (23/2574), according to RxISK